| The spinal muscular atrophies (SMAs) encompass a heterogeneous group of neurological disorders characterized by loss of anterior horn cells and muscle atrophy. SMAs can be distinguished by those with prominent proximal weakness and those with prominent distal weakness. The SMAs with prominent distal weakness are termed distal SMAs (dSMAs) and are often allelic with disorders such as Charcot-Marie-Tooth 2C (CMT-2C).;Proximal SMA is the leading inherited cause of infant mortality and is caused by loss of the survival of motor neuron (SMN) protein. In SMA mice, synaptic dysfunction of neuromuscular junctions (NMJs) and central sensorimotor synapses precedes synaptic disassembly and motor neuron cell death. We generated three lines of conditional SMA mice with tissue specific expression of SMN in motor neurons, muscle, or both to address if synaptic dysfunction is caused by SMN deficiency in motor neurons or muscle. All three lines of mice showed improvement in survival, weights, and motor behavior. Expression of SMN in motor neurons completely rescued NMJ and central synapse defects. Increased SMN expression in muscle did not improve synaptic abnormalities, although muscle growth was significantly improved. This study identified a critical role of SMN in motor neurons for NMJ and central synapse structure and function.;In a second study, mutations in the cation channel, transient receptor potential vanilloid-4 (TRPV4) were identified as the causative gene in CMT-2C/dSMA. Transfection of mutant TRPV4 in cultured cells resulted in increased calcium influx and cellular death. Interactions of mutant TRPV4 with known binding partners, Pacsin 3 and Calmodulin were not affected. Physiological studies in mutant TRPV4 transfected Xenopus oocytes exhibited increased constitutive and activated currents. This study identified a gain-of-function activity for mutant TRPV4 channel. |
